title: EPCAM germline and somatic rearrangements in Lynch syndrome: identification of a novel 3'EPCAM deletion.
abstract: 3'EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3'EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis. A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3'EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556-531_*872del) and one known EPCAM deletion (c.859-689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM-MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI-high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM-MSH2 region in the other tumor. This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors.
authors.affiliation: Department of Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium. marijke.spaepen@uzleuven.be
authors.forename: Marijke
authors.initials: M
authors.lastname: Spaepen
authors.forename: Esther
authors.initials: E
authors.lastname: Neven
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.forename: Eline
authors.initials: E
authors.lastname: Beert
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000235:genetics; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein